Proper brain function requires an active maintenance program to sustain neuronal health. In essence, neurons and glia have to repair the damage that is induced by neuronal activity, injury, toxins, and aging. Environmental stressors impact the nervous system and lead to neuronal dysfunction and degeneration if the protective mechanisms are weakened. Recent studies revealed that NMNATs (nicotinamide mononucleotide adenylyl transferase) maintain neuronal integrity and facilitate proper neural function throughout life. NMNAT2 is the major NMNAT isoform expressed in the mammalian brain and is extremely labile with a short half-life in neurons. We and others have found that NMNAT2 levels are significantly reduced in CNS tissues from patients with Alzheimer's disease, tauopathies, or Parkinson's disease. Reducing NMNAT2 function in mice leads to axonal deterioration, while NMNAT2 overexpression offers neuroprotection. In the proposed work we will address three specific aims: How does NMNAT2 reduce toxic tau species and protect neurons against tauopathy? Is NMNAT2 required to maintain neuronal health in adult brains? Is small molecule up-regulation of NMNAT2 levels neuroprotective? A combination of molecular/biochemical, genetic, anatomical, electrophysiological, imaging, viral vector and high-throughput screening approaches will be employed to accomplish these aims. This study will provide insight into how NMNAT2 maintains neuronal health in mature brains. NMNATs are potential drug targets for therapeutic interventions in neurodegeneration. A detailed knowledge on how NMNAT2 maintain neuronal integrity and its role in neuroprotection is critical not only for understanding normal brain function, but will also provide necessary insights to assist in drug discovery.